Gadolinium-based agents are used to enhance the contrast in images produced by MRI scanners. First concerns about gadolinium side effects emerged over a decade ago, after some patients with renal failure developed Nephrogenic Systemic Fibrosis (NSF) and a link was found between the "debilitating" condition and GBCA used in MRIs.
In September 2010, the FDA adopted safety label changes
including a contraindication for patients with renal insufficiency. FDA also encouraged healthcare professionals and patients to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program.
Then, in July 2015, the FDA issued a Drug Safety communication
that noted reports of retention of gadolinium in the brain after the use of GBCAs, which underscored the increased retention with linear GBCAs compared to macrocyclic GBCAs. In that communication the FDA urged physicians to limit the use of such agents to "clinical circumstances in which the additional information provided by the contrast is necessary," also urging them to reassess the necessity of repetitive contrast MRIs in established treatment protocols.
In May 2017, the FDA reported that a new review
showed that gadolinium is retained in brain and other body tissues, but no new adverse events were uncovered. Still, it stated that retention is greater for linear over macrocyclic GBCs and assessments are continuing as to whether reports of NSF in patients with normal kidney function are related to gadolinium retention. Accordingly, the FDA had announced to organize a public meeting to discuss this issue in the future.
Two months later, the European Medicines Agency (EMA) issued a final opinion
confirming restrictions on the use of the intravenous linear agents gadoxetic acid and gadobenic acid, as well as gadopentetic acid given intra-articularly. The EMA recommended the suspension of all other linear products.Public meeting
The announced public meeting took place last Friday, Sept. 8, 2016. During the all-day meeting, the committee heard from representatives of pharmaceutical industry, researchers, patients and patient advocacy groups. The meeting was also broadcasted over the internet.
During the meeting, some representatives of companies producing macrocyclic contrast agents sought to emphasize differences in the chemical structure between their products and linear contrast agents, which may lead to greater retention of linear products; while linear contrast agent manufacturers underscored that retention occurs with both classes, differences in retention are slight, and the threshold for toxicity is unclear.
Although the members of MIDAC overwhelmingly concluded there was not enough evidence to show a causal relationship between adverse symptoms and gadolinium retention, they still expressed their concerns.
"A lack of evidence is not evidence of safety," said Sonia Hernandez-Diaz, MD, Harvard TH Chan School of Public Health, Boston, Massachusetts.
At the end of the day-long meeting, committee members were asked to vote on whether they agreed with the FDA's plan to include a warning for all GBCAs, along with a warning that all or some of the linear versions may have greater retention than macrocyclics in certain organs.
"In spite of the lack of evidence, there is obvious concern in the medical community and industry and patient populations. I think it's important that information be put out there with regard to gadolinium retention," agreed Dr Herscovitch, MD, acting chair of the committee and director of the PET Department at the National Institutes of Health (NIH).
The overwhelming majority voted "yes" to the FDA plan. The lone "no" vote came from Alicia Toledano, ScD, president of Biostatistics Consulting, Kensington, Maryland. She said that the FDA's plan doesn't go far enough.
The one abstaining vote came from Sean Hennessy, PhD, PharmD. "I think the decision of whether or not linear agents should remain available is a risk-benefit decision, but we did not have that decision in a 1-day meeting," he said.
During the postvote discussion, two other committee members suggested, that the EMA proposal would have been another option that unfortunately was not at their deliberation.
Besides the recommendation for warning labels the committee also voted unanimously to recommend the FDA consider requiring industry conduct more research to help the agency determine if regulatory action "including withdrawal of approval and restriction of indicated populations" is necessary.